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2.
Am J Med Genet A ; 182(5): 962-973, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32031333

RESUMO

CDC42BPB encodes MRCKß (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.

3.
Am J Med Genet A ; 182(4): 866-876, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913576

RESUMO

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

4.
Genet Med ; 22(5): 878-888, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31949314

RESUMO

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

5.
Hum Mutat ; 41(1): 299-315, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31595648

RESUMO

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

6.
Am J Med Genet A ; 182(3): 597-606, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31825160

RESUMO

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

7.
Am J Med Genet A ; 182(1): 130-136, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680412

RESUMO

Costello syndrome (CS) is an autosomal-dominant condition caused by activating missense mutations in HRAS. There is little literature describing health concerns specific to adults with CS. Parents of individuals with CS need to know what to anticipate as their children age. We surveyed a group of 20 adults and older adolescents with CS regarding their medical concerns and lifestyle characteristics. We identified several previously undescribed actionable medical concerns in adults with CS. First, the high prevalence of anxiety in this cohort indicates that screening for anxiety is warranted since this is a treatable condition that can have a significant impact on quality of life. Second, adults with CS should be monitored for progressive contractures or other problems that could decrease mobility. This is especially important in a population that seems to have increased risk for osteopenia. Finally, the lack of cancer diagnoses in adulthood is of interest, although the cohort is too small to draw definitive conclusions about cancer risk in adults with CS. Ongoing follow-up of the current cohort of adults with CS is necessary to delineate progressive medical and physical problems, which is essential for providing targeted management recommendations and anticipatory guidance to families.

8.
Genet Med ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31723249

RESUMO

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

10.
Genet Med ; 21(12): 2807-2814, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31164752

RESUMO

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.

11.
Am J Hum Genet ; 104(6): 1139-1157, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31155282

RESUMO

Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.

12.
Am J Med Genet A ; 179(9): 1725-1744, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31222966

RESUMO

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

13.
Clin Epigenetics ; 11(1): 64, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029150

RESUMO

BACKGROUND: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included ~ 6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.

14.
Eur J Hum Genet ; 27(4): 582-593, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30622326

RESUMO

The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Exome sequencing revealed biallelic variants in INTS1 in all patients. One sib pair demonstrated a missense variant, p.(Arg77Cys), and a frameshift variant, p.(Arg1800Profs*20), another sib pair had a homozygous missense variant, p.(Pro1874Leu), and the fifth patient had a frameshift variant, p.(Leu1764Cysfs*16) and a missense variant, p.(Leu2164Pro). We also report additional clinical data on three previously described individuals with a homozygous, loss of function variant, p.(Ser1784*) in INTS1 that shared cognitive delays, cataracts and dysmorphic features with these patients. Several of the variants affected the protein C-terminus and preliminary modeling showed that the p.(Pro1874Leu) and p.(Leu2164Pro) variants may interfere with INTS1 helix folding. In view of the cataracts observed, we performed in-situ hybridization and demonstrated expression of ints1 in the zebrafish eye. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make larvae with biallelic insertion/deletion (indel) variants in ints1. The mutant larvae developed typically through gastrulation, but sections of the eye showed abnormal lens development. The distinctive phenotype associated with biallelic variants in INTS1 points to dysfunction of the integrator complex as a mechanism for intellectual disability, eye defects and craniofacial anomalies.

15.
Nat Med ; 25(1): 60-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617323

RESUMO

Syndromic genetic conditions, in aggregate, affect 8% of the population1. Many syndromes have recognizable facial features2 that are highly informative to clinical geneticists3-5. Recent studies show that facial analysis technologies measured up to the capabilities of expert clinicians in syndrome identification6-9. However, these technologies identified only a few disease phenotypes, limiting their role in clinical settings, where hundreds of diagnoses must be considered. Here we present a facial image analysis framework, DeepGestalt, using computer vision and deep-learning algorithms, that quantifies similarities to hundreds of syndromes. DeepGestalt outperformed clinicians in three initial experiments, two with the goal of distinguishing subjects with a target syndrome from other syndromes, and one of separating different genetic subtypes in Noonan syndrome. On the final experiment reflecting a real clinical setting problem, DeepGestalt achieved 91% top-10 accuracy in identifying the correct syndrome on 502 different images. The model was trained on a dataset of over 17,000 images representing more than 200 syndromes, curated through a community-driven phenotyping platform. DeepGestalt potentially adds considerable value to phenotypic evaluations in clinical genetics, genetic testing, research and precision medicine.


Assuntos
Aprendizado Profundo , Facies , Doenças Genéticas Inatas/diagnóstico , Algoritmos , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Fenótipo , Síndrome
16.
Mol Psychiatry ; 24(11): 1748-1768, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29728705

RESUMO

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

17.
Am J Hum Genet ; 104(1): 35-44, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554721

RESUMO

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.


Assuntos
Anormalidades Múltiplas/genética , Metilação de DNA/genética , Epigênese Genética/genética , Éxons/genética , Mutação , Pentosiltransferases/genética , Expansão das Repetições de Trinucleotídeos/genética , Alelos , Southern Blotting , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Sulfitos/metabolismo , Síndrome
18.
Hum Mutat ; 39(11): 1485-1493, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311384

RESUMO

The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan-like syndrome with loose anagen hair. The curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy.


Assuntos
Proteínas ras/metabolismo , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mutação/genética , Síndrome de Noonan/genética , Proteínas ras/genética
19.
Am J Med Genet A ; 176(12): 2787-2790, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30302924

RESUMO

Multiple mitochondrial dysfunction syndrome (MMDS) is a rare disorder of systemic energy metabolism associated with mutations in genes having a vital role in production of iron-sulfur clusters, important for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the mitochondrial respiratory chain complexes. MMDS 2 associated with BOLA3 mutation presents in early infancy and is characterized by developmental regression, severe encephalopathy, optic atrophy, and cardiomyopathy. Neuroimaging phenotype associated with MMDS 2 has never been described in its entirety in literature, with few reported cases till date. None of the published cases mention findings demonstrated in our case, a proband with biallelic BOLA3 variants, such as necrotic/cavitary lesions within the centrum semiovale, restricted diffusivity within the white matter, areas of central enhancement within the centrum semiovale presumably related to leakage of contrast within the necrotic center, enhancement of bilateral optic nerves, and markedly elevated lactate on magnetic resonance spectroscopy.


Assuntos
Diagnóstico por Imagem , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , Fenótipo , Proteínas/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Proteínas Mitocondriais , Tomografia Computadorizada por Raios X
20.
Am J Med Genet A ; 176(7): 1648-1656, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30160832

RESUMO

Aymé-Gripp syndrome (AGS) is an autosomal dominant multisystem disorder caused by specific heterozygous variants in MAF. The resulting aberrant protein shows impaired GSK-mediated MAF phosphorylation. AGS is characterized by congenital cataracts, sensorineural hearing loss, short stature, intellectual disability, and distinctive facial features with brachycephaly. Cardiac and joint phenotypes are present in nearly half of patients. We review information on 10 published individuals with MAF mutations and clinical AGS and describe five additional patients, including three with novel mutations. Joint problems, typically including radioulnar synostosis and joint limitations, were present in 9/15 patients. Hip replacement in young adulthood was needed in four patients. Pericarditis occurred in 6/15 individuals. An automated facial analysis of 2D photos was used to compare the facial phenotype of 13 individuals from the literature or reported here, with facial photos of a control cohort of unaffected individuals and a cohort of Down syndrome patients. A multiclass approach yielded an accuracy of 86.86% and 89.05%, respectively, in two independent experiments compared to a random chance of 37.74%. In binary comparisons of AGS and Down syndrome, the area under the curve (AUC) was 0.994 (P < .001) and 1.0 (P < .001), respectively. Binary comparisons of AGS and unaffected controls yielded AUC of 0.994 (P < .001) and 0.989 (P = .003), respectively, suggesting that the facial phenotype of AGS could clearly be distinguished from unaffected individuals and from Down syndrome patients. Automated facial analysis may be helpful in the identification and evaluation of individuals suspected to have AGS.


Assuntos
Catarata/genética , Catarata/patologia , Face/anormalidades , Face/patologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Adolescente , Adulto , Automação , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Facies , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Proteínas Proto-Oncogênicas c-maf/genética , Adulto Jovem
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